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Senolytic

Senolytics are a class of pharmacological agents designed to selectively induce apoptosis in senescent cells, which are viable cells that have permanently ceased dividing in response to various stressors such as DNA damage, oncogene activation, or telomere shortening, and accumulate in tissues over time. These cells contribute to aging and age-related diseases by secreting a range of pro-inflammatory cytokines, chemokines, and proteases collectively known as the senescence-associated secretory phenotype (SASP), which promotes chronic inflammation, tissue remodeling, and dysfunction in neighboring cells.^[1]^[2] The concept of senolytics emerged from foundational research in the early 2010s demonstrating that senescent cells resist programmed cell death through upregulated senescent cell anti-apoptotic pathways (SCAPs), including members of the BCL-2 family and p53/MDM2 interactions, creating exploitable vulnerabilities for targeted elimination.^[2] The first senolytics were identified in 2015 via high-throughput screening of FDA-approved compounds, revealing the tyrosine kinase inhibitor dasatinib and the flavonoid quercetin as effective in clearing senescent cells both in vitro and in mouse models of age-related conditions.^[3] Subsequent discoveries have expanded the repertoire to include navitoclax (a BCL-2 family inhibitor), fisetin (another flavonoid), HSP90 inhibitors like 17-AAG, and peptides such as FOXO4-DRI, each targeting distinct SCAP components or senescent cell surface markers to achieve specificity.^[1]^[4] Preclinical studies have demonstrated that intermittent senolytic treatment reduces senescent cell burden, mitigates SASP-driven inflammation, and improves physical function, tissue homeostasis, and lifespan in animal models of diseases including atherosclerosis, osteoarthritis, idiopathic pulmonary fibrosis, and neurodegeneration.^[2] For instance, dasatinib plus quercetin (D+Q) has alleviated frailty and extended healthspan in aged mice, while fisetin has shown efficacy in models of kidney disease and viral infection.^[1] Emerging approaches, such as immunotherapies (e.g., CAR-T cells targeting uPAR) and senolytic vaccines against antigens like GPNMB or CD153, aim to enhance precision and durability of clearance.^[1] As of November 2025, senolytics have advanced to human trials, with over 50 studies completed, ongoing, or planned for conditions like type 2 diabetes, sepsis, Alzheimer's disease, and age-related frailty, often using "hit-and-run" dosing to minimize off-target effects.^[5] Early-phase trials of D+Q have reported feasibility and preliminary benefits in reducing senescent cell markers and improving mobility or cognition in older adults, though challenges persist regarding toxicity (e.g., thrombocytopenia with navitoclax), optimal dosing, and long-term safety.^[6]^[7] Recent in vitro evidence also suggests senolytics can reverse epigenetic aging markers in human blood samples, underscoring their potential as a translational bridge between cellular senescence and organismal healthspan extension.^[8]

Background

Cellular Senescence

Cellular senescence is a stable and generally irreversible state of cell cycle arrest that prevents the proliferation of damaged or stressed cells, distinguishing it from quiescence, which is a reversible arrest, and apoptosis, which involves programmed cell death.31121-3) This process serves as a protective mechanism against tumorigenesis by halting the expansion of potentially harmful cells, but it can also contribute to tissue homeostasis when senescent cells are cleared by the immune system.^[9] The phenomenon was first systematically described in 1961 by Leonard Hayflick and Paul Moorhead, who observed that human diploid fibroblasts in culture undergo a finite number of divisions, termed the Hayflick limit, after which they enter a non-proliferative state.^[10] Several stressors can trigger cellular senescence, including persistent DNA damage from sources such as ionizing radiation or genotoxic agents, telomere shortening due to replicative exhaustion, activation of oncogenes like RAS, elevated oxidative stress from reactive oxygen species, and therapeutic interventions including chemotherapy and radiotherapy.31121-3) These triggers activate signaling pathways, notably involving p53/p21 and p16INK4a/Rb, which enforce the proliferative arrest through upregulation of cyclin-dependent kinase inhibitors.^[9] Senescent cells exhibit distinct hallmarks, including morphological alterations such as enlargement and flattening, increased expression of senescence-associated β-galactosidase (SA-β-gal) detectable at pH 6.0, and formation of senescence-associated heterochromatin foci (SAHF), which are discrete DAPI-stained nuclear domains that repress proliferation-associated genes.00401-X) SA-β-gal activity arises from lysosomal β-galactosidase and serves as a widely used biomarker for identifying senescent cells both in vitro and in vivo. SAHF formation involves histone modifications, such as H3K9me3 and HP1γ enrichment, contributing to stable gene silencing.00401-X) With advancing age, senescent cells accumulate progressively in various tissues, including skin, liver, and adipose tissue, leading to functional decline and impaired tissue regeneration.^[11] This buildup is evidenced by increased SA-β-gal-positive cells in aged human samples, correlating with chronological age across multiple organs.^[12] Senescent cells often develop a senescence-associated secretory phenotype (SASP), releasing pro-inflammatory cytokines and proteases that can influence the surrounding microenvironment.31121-3)

Role in Aging and Disease

Cellular senescence serves a dual role in biology, acting as a protective mechanism during development and early life while contributing to pathology when cells accumulate persistently. In physiological contexts, senescent cells promote tumor suppression by halting the proliferation of potentially cancerous cells and facilitate wound healing and tissue remodeling by recruiting immune cells to clear debris and support repair.30546-9) However, chronic accumulation of senescent cells in aging tissues shifts this response to a detrimental state, where their persistence drives degenerative processes rather than resolution.^[13] Senescent cells contribute to several hallmarks of aging through the senescence-associated secretory phenotype (SASP), a complex mix of cytokines, chemokines, and proteases such as IL-6, IL-8, and matrix metalloproteinases (MMPs). The SASP induces chronic low-grade inflammation, known as inflammaging, which propagates senescence to neighboring healthy cells and impairs tissue function.^[14] Additionally, SASP factors disrupt stem cell niches, leading to exhaustion and reduced regenerative capacity, while promoting excessive extracellular matrix remodeling that culminates in fibrosis across various organs.^[13] The pathological effects of senescent cells manifest in multiple age-related diseases. In atherosclerosis, vascular endothelial and smooth muscle cells undergo senescence, exacerbating plaque formation and arterial stiffness through inflammatory signaling.^[15] Osteoarthritis involves senescent chondrocytes in joint tissues, which secrete degradative enzymes that accelerate cartilage breakdown.^[15] In neurodegeneration, senescent glial cells in the brain contribute to neuroinflammation and neuronal loss, as seen in conditions like Alzheimer's disease.^[16] Furthermore, therapy-induced senescence in cancer can paradoxically foster tumor relapse by creating a pro-tumorigenic microenvironment via SASP-mediated immunosuppression.^[15] Evidence from animal models and human studies underscores the link between senescent cell burden and aging phenotypes. In progeroid BubR1 mutant mice, which exhibit accelerated aging, p16^Ink4a-positive senescent cells accumulate prematurely in multiple tissues, correlating with frailty and organ dysfunction; genetic clearance of these cells delays disease onset. Similarly, human biopsies from aged individuals reveal elevated senescent cell markers, such as increased β-galactosidase activity and p16^Ink4a expression, in tissues like skin, adipose, and liver, supporting their role in natural aging.^[17] From an evolutionary viewpoint, senescence likely evolved as an adaptive response to limit damage from oncogenic or stressful events, but becomes maladaptive in post-reproductive life when clearance mechanisms decline.^[18]

Definition and Mechanisms

What are Senolytics

Senolytics are pharmacological agents designed to selectively induce apoptosis in senescent cells, thereby clearing them from tissues while sparing healthy cells.^[19] This selective action exploits the unique biology of senescent cells, which, despite their resistance to programmed cell death, upregulate specific anti-apoptotic pathways that can be targeted to restore their susceptibility to apoptosis.^[19] The concept of senolytics was first coined in 2015 by a team led by James L. Kirkland and colleagues, who identified candidate compounds through transcriptomic analysis of senescent cells, revealing their reliance on pro-survival networks such as those involving the Bcl-2 family of proteins.^[19] That same year marked the initial in vivo demonstration of senolytic efficacy, with dasatinib plus quercetin clearing senescent cells in progeroid mouse models and alleviating age-related dysfunction.^[19] A key feature of senolytic therapy is its "hit-and-run" dosing strategy, involving intermittent administration to periodically eliminate accumulated senescent cells while minimizing exposure and off-target effects on non-senescent cells. Unlike continuous treatments aimed at preventing senescence or suppressing its effects, senolytics prioritize the physical removal of these cells to mitigate their detrimental contributions to aging and disease.

Molecular Targets

Senescent cells develop resistance to apoptosis through the upregulation of pro-survival networks, including the BCL-2 family proteins Bcl-2 and Bcl-xL, as well as survivin, which collectively inhibit programmed cell death and promote cell persistence. This apoptosis resistance is a hallmark feature distinguishing senescent cells from their non-senescent counterparts, enabling their accumulation in tissues during aging and disease. Central to this resistance is the senescence-associated anti-apoptotic pathway (SCAP) network, which integrates multiple pro-survival signaling cascades upregulated in senescent cells. Key components include the PI3K/AKT pathway, which enhances cell survival signals, and the interaction between p53 and FOXO4, where FOXO4 sequesters p53 in the nucleus to prevent its pro-apoptotic functions. Senescent cells also exhibit a heightened dependency on specific BCL family proteins within this network, making these pathways prime targets for selective elimination. Senolytics exploit these dependencies by inhibiting BCL-2 family proteins, such as through BH3 mimetics that bind and neutralize anti-apoptotic members, thereby restoring the apoptotic balance in senescent cells. Another approach involves disrupting the FOXO4-p53 interaction with peptides that release p53, allowing its translocation to mitochondria to initiate apoptosis selectively in senescent cells.^[20] In vitro evidence supports this selectivity, with senescent cells demonstrating substantially higher sensitivity to BCL inhibitors compared to proliferating cells, highlighting their unique vulnerabilities.^[19] Recent studies have elucidated how mitochondrial dysfunction and elevated reactive oxygen species (ROS) further amplify senolytic vulnerability in senescent cells. Impaired mitochondrial oxidative phosphorylation in these cells leads to ROS accumulation, which exacerbates stress and sensitizes them to pro-apoptotic interventions targeting the SCAP network.^[21] This metabolic shift provides an additional layer of specificity, as non-senescent cells maintain better ROS homeostasis and are less affected.^[21]

Senolytic Agents

First-Generation Senolytics

First-generation senolytics refer to the initial class of compounds identified through targeted screening efforts in the mid-2010s, primarily using senescent human cell lines such as IMR-90 lung fibroblasts induced by stressors like irradiation or oncogene activation, followed by viability assays to measure selective cell death post-drug exposure.^[22] These early methods focused on hypothesis-driven approaches targeting senescent cell anti-apoptotic pathways (SCAPs), including brief interrogation of BCL family proteins that confer survival advantages to senescent cells.^[22] The combination of dasatinib and quercetin (D+Q) emerged as a prototype senolytic in 2015 from high-throughput screens of FDA-approved drugs and natural compounds on multiple senescent cell types, including IMR-90 fibroblasts and human endothelial cells.^[22] Dasatinib, a tyrosine kinase inhibitor originally developed for chronic myeloid leukemia, is administered orally with rapid absorption and FDA approval since 2006 for its anticancer indications.^[23] Quercetin, a flavonoid polyphenol found in fruits and vegetables, complements dasatinib by targeting additional SCAPs but exhibits low oral bioavailability, which can be enhanced through liposomal formulations to improve absorption and tissue delivery in senolytic contexts.^[24] Navitoclax (ABT-263), another foundational senolytic, was repurposed from cancer research as a potent inhibitor of BCL-2, BCL-xL, and BCL-w anti-apoptotic proteins, demonstrating high efficacy in clearing senescent fibroblasts such as IMR-90 cells by restoring apoptosis susceptibility. Developed initially for lymphoid malignancies, its senolytic activity was confirmed in preclinical models where it reduced senescent cell burden without broadly affecting proliferating cells. However, navitoclax induces thrombocytopenia as a dose-limiting side effect due to BCL-xL inhibition in platelets, constraining its chronic use.^[25] Fisetin, a natural polyphenol abundant in strawberries, was identified as a senolytic in 2018 through screening of flavonoids for superior potency against senescent cells, acting primarily via inhibition of BCL family proteins to promote their clearance.^[26] In late-life administration to wild-type mice, fisetin extended median lifespan by approximately 10% while reducing age-related pathology in multiple tissues, highlighting its broad senotherapeutic potential.^[26] Pre-2020 developments for D+Q included initial patents held by the Mayo Clinic covering its use as a senolytic agent, alongside its investigational status in early human trials for age-related conditions, leveraging dasatinib's established safety profile.^[27]

Emerging Candidates

Recent advancements in senolytic research have leveraged artificial intelligence and high-throughput screening to identify novel compounds targeting key anti-apoptotic pathways in senescent cells. In a 2023 study utilizing deep neural networks to screen over 800,000 small molecules against BCL-2 family proteins, three compounds—BRD-K20733377, BRD-K56819078, and BRD-K44839765—emerged as potent senolytics with enhanced selectivity for senescent cells in vitro.^[28] These AI-discovered agents inhibit BCL-2, promoting apoptosis in senescent cells while sparing proliferating ones, as demonstrated in models of therapy-induced senescence, where they reduced senescent cell burden by up to 50% without significant toxicity to healthy tissues. Natural compounds have also gained attention as emerging senolytics, with piperlongumine, an alkaloid derived from long pepper, showing preclinical efficacy in clearing senescent cells through reactive oxygen species induction and glutathione depletion. Recent optimizations of piperlongumine analogs in 2023 demonstrated improved potency, selectively eliminating senescent fibroblasts and reducing senescence-associated secretory phenotype (SASP) markers in wound healing models.^[29] While clinical translation remains early, these findings highlight piperlongumine's potential for frailty-related applications due to its low toxicity profile in non-senescent cells. Peptide-based senolytics represent another innovative class, particularly those disrupting FOXO4-p53 interactions to restore apoptosis in senescent cells. The FOXO4-DRI peptide, initially developed in 2017, sequesters p53 from nuclear retention by FOXO4, inducing selective cell death in senescent populations. Between 2023 and 2025, structural studies and delivery optimizations, including cell-penetrating conjugates, enhanced its specificity and bioavailability.^[30] In vitro assays have shown substantial clearance of senescent chondrocytes (reducing senescent proportion from >40% to <5%) without affecting healthy cells.^[31] These refinements address previous challenges in tissue penetration, positioning FOXO4-related peptides as promising for age-related degenerative diseases. High-throughput screens conducted in 2024 have uncovered additional novel classes exploiting metabolic and proteolytic vulnerabilities of senescent cells. USP7 inhibitors, such as P5091, stabilize p53 by preventing its deubiquitination, leading to apoptosis in senescent human dermal fibroblasts under high-glucose conditions, as evidenced by a 40-60% reduction in senescence markers like SA-β-gal in diabetic wound models.^[32] Similarly, GLS1 inhibitors like CB-839 target glutaminolysis, a metabolic dependency in senescent cells; 2024 studies showed CB-839 eliciting 30-50% senolysis in therapy-induced senescent melanoma cells by depleting glutamine-derived metabolites essential for survival.^[33] Cardiac glycosides, including ouabain, were identified in 2019 high-throughput screens as broad-spectrum senolytics, sensitizing senescent cells to calcium-mediated apoptosis via Na+/K+-ATPase inhibition, with preclinical data indicating efficacy in reducing senescent burden in lung fibrosis models.^[34] Immuno-senolytic approaches, integrating senolytics with cellular therapies, have advanced with chimeric antigen receptor (CAR)-T cells engineered to target surface markers on senescent cells. Preclinical studies from 2020 demonstrated that CAR-T cells directed against uPAR (urokinase plasminogen activator receptor) effectively ablate uPAR-positive senescent cells in liver and lung fibrosis models, restoring tissue homeostasis and reducing fibrosis by approximately 50% in liver models and 40% in lung models in mice.^[35] Targeting DPP4 (dipeptidyl peptidase-4), another senescence-associated marker, has shown similar promise in vitro, with CAR-T constructs selectively eliminating senescent endothelial cells and mitigating vascular aging phenotypes. These strategies offer durable, targeted clearance, potentially requiring only intermittent dosing for sustained effects.^[36]

Research and Clinical Trials

Preclinical Studies

Preclinical studies of senolytics have primarily utilized mouse models to demonstrate selective clearance of senescent cells, resulting in reduced tissue dysfunction and improved physiological outcomes in aging and disease contexts. Early investigations identified dasatinib and quercetin (D+Q) as effective senolytics, with in vivo administration reducing senescent cell burden in adipose tissue of aged mice by targeting anti-apoptotic pathways like BCL-2 family members and Src kinases. This clearance led to decreased expression of senescence-associated markers, including p16^INK4a and senescence-associated β-galactosidase (SA-β-gal), alongside diminished secretion of the senescence-associated secretory phenotype (SASP) factors such as IL-6 and MMPs. In models of diet-induced obesity, intermittent D+Q treatment cleared senescent cells from adipose tissue, achieving 30-60% reductions in p16^INK4a-positive cells and SASP markers, which improved metabolic function by enhancing insulin sensitivity, glucose tolerance, and adipocyte proliferation while lowering systemic inflammation. Similarly, in progeroid mouse models like Ercc1^−/∆, senolytic interventions, including D+Q, alleviated accelerated aging phenotypes, extended healthspan through better physical function and tissue rejuvenation, and increased median lifespan by up to 25% via reduced senescence-driven fibrosis and inflammation. Disease-specific preclinical evidence highlights senolytics' potential in organ-specific pathologies. In a bleomycin-induced model of idiopathic pulmonary fibrosis, clearance of senescent cells decreased fibrotic burden, improved lung function, and reduced SASP-mediated extracellular matrix deposition, with p16^INK4a and SA-β-gal markers dropping by 40-50% post-treatment.^[37] For atherosclerosis in ApoE^−/− mice fed a high-fat diet, D+Q administration reduced senescent vascular smooth muscle cells and endothelial cells in plaques, attenuating lesion progression and enhancing plaque stability without altering lipid profiles. In tauopathy models such as PS19 mice, senolytic therapy diminished glial senescence, lowered tau hyperphosphorylation and neuroinflammation, and preserved cognitive performance, with SASP components like IL-1β decreasing by over 30%. Fisetin, another senolytic, has shown comparable neuroprotective effects in brief evaluations of neurodegeneration models.^[38] Dosage regimens in these studies favor intermittent administration to minimize toxicity while maximizing efficacy, such as weekly oral D+Q (5 mg/kg dasatinib + 50 mg/kg quercetin) for 3-11 doses, which consistently achieved 20-50% senescent cell reductions across tissues without off-target effects in young mice. Investigations have confirmed that such hit-and-run protocols sustain SASP suppression and tissue rejuvenation for weeks post-treatment, outperforming continuous dosing in preserving proliferative capacity.^[39] Despite these advances, preclinical models reveal limitations, including lower baseline senescence burden in mice compared to humans, potentially underestimating translational efficacy, and modest lifespan extensions of 10-15% in naturally aged wild-type mice, with longer-term data remaining sparse beyond short-term healthspan gains.

Human Trials

Human clinical trials of senolytics have primarily focused on early-phase studies evaluating safety, feasibility, and preliminary efficacy in age-related conditions. The first-in-human trial of the senolytic combination dasatinib plus quercetin (D+Q) was conducted in 2019 as a phase I open-label pilot in individuals with diabetic kidney disease, involving intermittent dosing over three weeks. This study demonstrated a reduction in senescent cell markers, such as senescent cell anti-apoptotic pathway components and p16^INK4a expression in adipose tissue, supporting the translation of preclinical findings to humans.^[40] A subsequent phase I pilot trial in 2019, later followed by a randomized placebo-controlled phase I study reported in 2023, evaluated D+Q in patients with idiopathic pulmonary fibrosis (IPF). The intervention led to improved physical function, including better performance on the 6-minute walk test and reduced frailty index scores, alongside evidence of alveolar simplification on imaging.^[41]^[42] Recent updates from 2024-2025 trials have provided further insights into senolytics' effects on specific age-related phenotypes. A phase II randomized controlled trial funded by the National Institute on Aging (NIA), completed in early 2025, tested intermittent D+Q in postmenopausal women to assess bone health. The study observed subtle benefits, including minor reductions in bone resorption markers like C-terminal telopeptide, though overall impacts on bone mineral density were limited.^[43]^[44] Similarly, a single-arm pilot trial published in February 2025 examined D+Q in older adults at risk for Alzheimer's disease, focusing on cognition and mobility. The regimen was feasible and safe, with preliminary evidence of gait speed improvements and no serious adverse events interrupting treatment.^[45] As of late 2025, over 30 senolytic clinical trials are registered on ClinicalTrials.gov, encompassing various agents and indications, including a phase 2B trial of UBX1325 for diabetic macular edema that reported safety and potential efficacy in earlier-stage cases as of November 2025.^[46] For instance, NCT04313634 investigates D+Q for skeletal health in older women, measuring changes in bone turnover markers. A September 2025 commentary in Nature Aging highlights the need for personalized approaches in these trials, such as biomarker-guided patient selection to optimize efficacy across heterogeneous populations.^[47]^[48] Biomarkers for assessing senescent cell burden in human trials include circulating senescence-associated β-galactosidase (SA-β-gal) activity, p16^INK4a expression in peripheral blood mononuclear cells, and SASP components like IL-6 and CXCL8 cytokines. These markers have shown responsiveness to senolytic treatment in early studies, but challenges persist in their quantification due to low circulating levels, assay variability, and lack of tissue-specific validation.^[5]^[49] Adverse events in D+Q trials have generally been mild, including transient fatigue and nausea, resolving without intervention. In contrast, navitoclax trials report rare but notable thrombocytopenia, typically dose-dependent and reversible upon discontinuation.^[50]^[51]

Senomorphics

Senomorphics represent a class of therapeutic agents designed to suppress the senescence-associated secretory phenotype (SASP), a hallmark of cellular senescence characterized by the secretion of pro-inflammatory factors, thereby mitigating the detrimental paracrine effects of senescent cells without inducing their elimination. Unlike senolytics, which target senescent cell clearance, senomorphics modulate the harmful secretory output to reduce tissue dysfunction and chronic inflammation associated with aging and disease. This approach preserves the beneficial tumor-suppressive roles of senescent cells while addressing their pathological contributions.^[52] The primary mechanisms of senomorphics involve the inhibition of key signaling pathways that drive SASP production, including NF-κB, JAK/STAT, and mTOR, which collectively regulate the transcription and secretion of pro-inflammatory cytokines such as IL-6 and TNF-α. For instance, mTOR inhibition disrupts protein synthesis and IL-1α/NF-κB feedback loops essential for SASP amplification, while JAK/STAT blockade attenuates cytokine signaling, and NF-κB suppression directly curbs inflammatory gene expression. These interventions selectively dampen SASP components without altering the core senescent state, such as cell cycle arrest.^[53]^[54] Prominent examples include rapamycin, an mTOR inhibitor first demonstrated to suppress SASP in 2015 studies on irradiated human fibroblasts, where it reduced secretion of IL-6 and other factors without affecting cell viability. In mouse models, rapamycin delayed the onset of senescence-associated phenotypes, such as age-related frailty, by limiting SASP-driven inflammation, as evidenced in dietary restriction mimetic experiments. Metformin, acting as an AMPK activator, similarly inhibits SASP by repressing mTOR and NF-κB pathways, with preclinical data showing reduced cytokine output in senescent endothelial cells. Apigenin, a flavonoid that suppresses NF-κB activation via IRAK1/4 and p38 MAPK inhibition, effectively lowers SASP levels in various cell types, including therapy-induced senescent fibroblasts.^[55]^[56]^[57]^[58] Compared to senolytics, senomorphics offer potential advantages, including fewer risks of off-target apoptotic effects in non-senescent cells and greater reversibility upon treatment cessation, as they do not permanently eliminate cell populations. This makes them suitable for chronic administration in age-related conditions, though long-term safety profiles require further validation in clinical settings.^[52]^[59]

Immunotherapies and Other Strategies

Immunotherapies represent a promising class of senolytic strategies that leverage the immune system to selectively eliminate senescent cells by targeting their unique surface markers, such as urokinase-type plasminogen activator receptor (uPAR) and dipeptidyl peptidase 4 (DPP4). Unlike small-molecule senolytics that act intracellularly, these approaches enhance precision by engaging immune effectors to recognize and clear senescent cells without broadly affecting healthy tissues.^[60]^[61] Chimeric antigen receptor (CAR) T-cell therapies have emerged as a leading immunotherapy for senescent cell clearance. Engineered T cells expressing CARs directed against uPAR, a marker upregulated on senescent cells, have demonstrated prophylactic and long-lasting efficacy in preclinical models of aging and disease. In mouse models of physiological aging, uPAR-targeted CAR T cells improved exercise capacity and ameliorated metabolic dysfunction, such as enhancing glucose tolerance, with no observed systemic toxicity.^[60]^[62] Similarly, in liver fibrosis models, uPAR-CAR T cells significantly reduced extracellular matrix deposition and improved liver function by clearing senescent cells in targeted tissues.^[61] These therapies highlight the potential of adoptive cell transfer to achieve durable senescent cell ablation, with ongoing research exploring NKG2D-CAR T cells for stress-induced senescence.^[63] Peptide-based strategies offer a complementary approach by mimicking natural ligands to promote phagocytosis of senescent cells via the CD47-SIRPα axis. Thrombospondin-1 (TSP-1) mimetic peptides, such as 4N1K, bind to CD47 on senescent cell surfaces, disrupting the "don't eat me" signal and facilitating macrophage-mediated clearance. In preclinical models, 4N1K-decorated nanosystems selectively targeted senescent cells, inducing their death without affecting non-senescent populations, as demonstrated in 2022 studies on sphingomyelin nanoparticles.^[64] Recent investigations, including 2024 analyses, have extended this to cancer relapse prevention, where 4N1K peptides acted as senolytics to eliminate therapy-induced senescent cells, reducing their escape and metastatic potential.^[65] This mechanism provides a non-cytotoxic, immune-engaging alternative that enhances natural clearance pathways.^[66] Hybrid approaches combine immunological targeting with drug delivery to amplify senolytic effects. Senolytic vaccines, such as nanovaccines loaded with senescent cell antigens (e.g., GK-NaV), induce adaptive immune responses that specifically clear senescent cells, as shown in 2025 preclinical studies where they reduced senescent burden in aging tissues.^[67] Nanoparticles delivering combinations like dasatinib and quercetin (D+Q) via uPAR-targeted systems have improved bioavailability and specificity, enhancing clearance in senescent tumor models without off-target effects.^[68] Additionally, senescent cell-specific prodrugs, activated by biomarkers like β-galactosidase, have been developed in self-assembling nanoparticle formats, achieving selective apoptosis in 2025 in vitro and ex vivo models of age-related diseases.^[69] These hybrids bridge vaccine-induced immunity and targeted pharmacology for multifaceted clearance.^[70] Nanotherapies, including antibody-drug conjugates (ADCs), further refine precision by linking senescent antigens to cytotoxic payloads. ADCs targeting β2-microglobulin (B2M), a surface marker on senescent cells, release toxins like duocarmycin selectively within targeted cells, effectively clearing senescent cells in preclinical assays without toxicity to healthy cells.^[71] Early 2025 developments have advanced DPP4-targeted nanoparticles and ADCs, which conjugate antibodies to senolytic toxins, demonstrating reduced senescent cell occurrence in fibrosis and cancer models.^[72]^[73] These strategies emphasize surface marker specificity, enabling immune-mediated or direct toxic clearance with minimal systemic impact.^[74] Overall, immunotherapies and related strategies distinguish themselves by exploiting senescent cell surfaceome alterations for targeted immune engagement or delivery, contrasting with intracellular small-molecule mechanisms and offering reduced off-target risks in clinical translation.^[75]^[76]

Therapeutic Potential and Challenges

Potential Applications

Senolytic agents hold promise for addressing a wide array of age-related diseases, with preclinical and early clinical evidence suggesting efficacy across more than 70 such conditions, including frailty, osteoporosis, and cardiovascular disease.^[77] In frailty, a 2025 pilot study demonstrated improvements in mobility among older adults at risk for Alzheimer's disease following intermittent senolytic treatment, highlighting potential benefits for physical resilience in aging populations.00056-8/fulltext) For osteoporosis, senolytics have shown subtle enhancements in bone formation markers, such as procollagen type 1 N-terminal propeptide (P1NP), in postmenopausal women, indicating a role in mitigating bone loss without overt structural changes.^[43] In cardiovascular disease models, senolytics like navitoclax have reduced atherosclerotic plaque size and improved plaque stability in mice, suggesting mechanisms to counteract vascular senescence.00280-8/fulltext) Beyond specific pathologies, senolytics offer broader benefits for healthy aging, including enhanced physical function, reduced systemic inflammation, and potential lifespan extension. In mouse models, intermittent senolytic administration has extended median lifespan by 10-30%, depending on the agent and dosing regimen, by alleviating senescence-driven dysfunction.^[78] Recent 2025 reviews emphasize these effects in promoting healthspan, linking senolytic clearance of senescent cells to decreased inflammaging and improved tissue homeostasis across multiple organs.^[79] Senolytics can serve both therapeutic and preventive roles, with intermittent dosing strategies enabling prophylaxis in at-risk groups. For example, post-chemotherapy administration may prevent therapy-induced senescence and associated frailty in cancer survivors, preserving long-term physical function.30062-3/fulltext) For instance, the combination of dasatinib and quercetin (D+Q) has been evaluated in clinical trials for diabetic kidney disease, demonstrating feasibility for targeted interventions.30641-3/fulltext) Emerging 2025 approaches in personalized medicine aim to tailor senolytic therapies based on individual senescence burden, using biomarkers like SASP factors or p16^INK4a expression to identify responders and optimize dosing.^[7] On a societal level, senolytics could alleviate multimorbidity in aging populations, potentially reducing the economic burden of chronic diseases by minimizing concurrent health declines and extending productive lifespan.^[80]

Safety Concerns and Future Directions

One major safety concern with senolytics is the potential for off-target apoptosis in healthy, non-senescent cells, which can lead to unintended toxicities. For instance, BCL-2 family inhibitors like navitoclax, while effective against senescent cells, induce apoptosis in platelets due to their high expression of BCL-XL, resulting in thrombocytopenia that limits dosing and clinical use.^[81]^[82] Additionally, senolytics may disrupt beneficial roles of senescence in physiological processes such as wound healing and embryogenesis, where transient senescence coordinates tissue remodeling and repair; indiscriminate clearance could impair these functions, emphasizing the need for selective targeting.^[21]^[83]^[84] Key challenges in senolytic development include the heterogeneity of senescent cells across tissues and stressors, which upregulate diverse anti-apoptotic pathways, often necessitating multi-target agents to achieve broad efficacy rather than single-pathway inhibitors.^[73] Delivery to protected tissues like the brain poses further hurdles, as the blood-brain barrier restricts many small-molecule senolytics, potentially limiting their impact on central nervous system senescence.^[85] Moreover, long-term effects remain largely unknown, with current data derived primarily from short-term preclinical models and early human studies, raising questions about sustained safety and potential cumulative risks.^[76]^[86] As of 2025, significant gaps persist in the field, including the absence of Phase III trials to confirm efficacy and safety at scale, which hinders regulatory approval for broader indications.^[87] There is also a pressing need for validated biomarkers to reliably detect senescent cell burden and monitor treatment responses, given the lack of universal markers amid cellular heterogeneity.^[88] Ethical concerns arise in applying senolytics for healthy aging, balancing potential enhancements in lifespan against risks of unintended consequences and equitable access, particularly since aging itself is not classified as a disease.^[89]^[90] Future directions include leveraging artificial intelligence and machine learning to design pan-senolytic compounds that address multiple anti-apoptotic pathways while minimizing off-target effects, with recent models already predicting novel candidates from phenotypic data.^[91] Combining senolytics with senomorphics—agents that suppress the senescence-associated secretory phenotype (SASP) without cell clearance—could offer synergistic benefits, modulating harmful inflammation while preserving transient senescence where needed.^[73] Establishing regulatory pathways for anti-aging indications will require redefining endpoints around healthspan metrics, potentially through adaptive trial designs that integrate surrogate biomarkers.^[92] To mitigate risks, recommendations emphasize intermittent dosing regimens, which reduce toxicity compared to continuous administration by allowing senescent cell repopulation between cycles while targeting accumulated burdens.^[93] Ongoing monitoring of SASP factors, such as IL-6 and MMPs, via fluid biomarkers could guide dosing and assess efficacy in real-time.^[5] Finally, longitudinal studies in diverse populations are essential to elucidate long-term outcomes, including impacts on immune function and frailty.^[94] Recent trials have reported only mild adverse events with such approaches, supporting their feasibility.^[5]

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The senescent cell (SNC) fate has been linked to several beneficial processes, including wound resolution, embryogenesis and cancer prevention. Permanent ...Senescence And Age-Related... · Senolysis: Eliminating Sncs · Existing Senolytics<|control11|><|separator|>
[15]
Cellular senescence in brain aging and neurodegenerative diseases
a... · Outlook
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Tissue specificity of senescent cell accumulation during physiologic ...
Jan 25, 2020 · Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence-associated secretory phenotype (SASP).
[17]
The metabolic roots of senescence: mechanisms and opportunities ...
Oct 18, 2021 · Adaptive vs maladaptive effects of senescent cells. The senescence response can be beneficial or deleterious, depending on the physiological ...
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The Achilles' heel of senescent cells: from transcriptome to senolytic ...
Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By ...
[19]
Current senolytics: Mode of action, efficacy and limitations, and their ...
In this review, we have gathered and classified the proposed senolytics and discussed their mechanisms of action.
[20]
The Achilles' heel of senescent cells: from transcriptome to senolytic ...
Mar 9, 2015 · ... senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in ...Senolytic Sirnas · Candidate Senolytic Drugs In... · Effects Of Senolytic Agents...Missing: definition | Show results with:definition
[21]
[PDF] SPRYCEL (dasatinib) tablets label - accessdata.fda.gov
Based on pharmacokinetic studies, a dose decrease to 20 mg daily should be considered for patients taking SPRYCEL 100 mg daily. For patients taking SPRYCEL 140 ...
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Recent Advances in Potential Health Benefits of Quercetin - MDPI
The potential of liposomes to enhance the bioactivity and bioavailability of quercetin has been the subject of several investigations [188,189,190]. It has ...4. Biological Activities · 4.1. Antioxidant Activity · 4.2. Anticancer Activity
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The Senolytic Drug Navitoclax (ABT-263) Causes Trabecular Bone ...
May 20, 2020 · However, navitoclax is also a chemotherapeutic agent, with reported toxic side effects including transient thrombocytopenia and neutropenia ( ...
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Fisetin is a senotherapeutic that extends health and lifespan
Taken together, these studies demonstrate that senolytic compounds can have significant effects on chronic degenerative diseases and age-related pathology.
[25]
Senolytic drugs: from discovery to translation - Kirkland - 2020
Jul 19, 2020 · Senolytics are a class of drugs that selectively clear senescent cells (SC). The first senolytic drugs Dasatinib, Quercetin, Fisetin and Navitoclax were ...Missing: definition Kirtland
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The disordered p53 transactivation domain is the target of FOXO4 ...
Jul 1, 2025 · This study reveals structural insights into p53 binding to FOXO4/FOXO4-DRI, informing the development of p53-targeted senolytics for age related diseases.
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Targeting senescent HDF with the USP7 inhibitor P5091 ... - PubMed
Aug 30, 2024 · This study clarified the molecular mechanism of USP7 inhibitor (P5091) selectively inducing apoptosis of high glucose senescent HDF cells.
[28]
Inhibition of glutaminase elicits senolysis in therapy-induced ...
Dec 18, 2024 · We demonstrated that inhibition of GLS1 by CB-839 eliminated 30–50% of palbociclib-induced senescent BrafWTNrasWT and BrafV600E melanoma ...
[29]
Identification and characterization of Cardiac Glycosides as ... - Nature
Oct 21, 2019 · We decided to confront Proscillaridin A, Ouabain, one of the most studied CGs, and Digoxin for their relative senolytic activity. Using A549 ...
[30]
Therapeutic targeting of senescent cells in the CNS - PubMed Central
Utilizing uPAR as a target antigen, CAR-T cells have been shown to effectively clear senescent cells, mitigating various pathologies in mouse models of ...
[31]
Cellular senescence mediates fibrotic pulmonary disease - Nature
Feb 23, 2017 · Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves ...
[32]
Combination of dasatinib and quercetin improves cognitive abilities ...
The natural senolytic fisetin and a combination of dasatinib and quercetin (D+Q) treatment improve cognitive ability in mouse models of Alzheimer's disease and ...
[33]
Long-term treatment with senolytic drugs Dasatinib and Quercetin ...
Sep 3, 2021 · We explored the ability of the Dasatinib and Quercetin drug combination (D + Q) to prevent an age-dependent progression of disc degeneration in mice.
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Senolytics decrease senescent cells in humans - PubMed - NIH
Sep 18, 2019 · Senolytics decrease senescent cells in humans: Preliminary report ... Electronic address: Kirkland.James@Mayo.edu. PMID: 31542391; PMCID ...Missing: 2015 | Show results with:2015
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Senolytics in idiopathic pulmonary fibrosis: Results from a ... - PubMed
Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice. Methods: A two- ...
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Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis
Intermittently-dosed D + Q in patients with IPF is feasible and generally well-tolerated. Further prospective studies, such as a larger RCT, are needed.
[37]
Effects of intermittent senolytic therapy on bone metabolism in ...
Jul 2, 2024 · We conducted a phase 2 randomized controlled trial of intermittent administration of the senolytic combination dasatinib plus quercetin (D + Q) in ...
[38]
Senolytic therapy shows subtle impact on age-related bone health in ...
Feb 27, 2025 · An NIA-funded clinical trial investigating whether senolytics could improve bone health in older women had just subtle results.Missing: elderly | Show results with:elderly
[39]
Study Details | NCT04313634 | Targeting Cellular Senescence With ...
Study Overview To determine if senolytic drugs reduce senescent cell burden and reduce bone resorption markers/increase bone formation markers in elderly women.
[40]
Characterization of Human Senescent Cell Biomarkers for Clinical ...
Our findings provide further support for the T‐cell p16_variant 5 assay as a biomarker for selecting participants in clinical trials of senolytic interventions.1. Introduction · 2.4. Bulk Mrna Sequencing... · 3. ResultsMissing: cytokines | Show results with:cytokines
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Biomarkers of Cellular Senescence and Aging: Current State‐of‐the ...
Jun 27, 2024 · This review focused on the applications and limitations of major senescence biomarkers, including senescence-associated β-galactosidase ...2 Biomarkers For Senescence · 2.2 Telomere Shortening · 3.1 Senolytic Drugs
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The Senolytic Drug Navitoclax (ABT-263) Causes Trabecular Bone ...
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Targeting cellular senescence with senotherapeutics: senolytics and ...
Jan 11, 2022 · Here, we review the current state of the development of senolytics and senomorphics for the treatment of age-related diseases and disorders and extension of ...
[44]
Nutritional senolytics and senomorphics: Implications to immune ...
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[45]
JAK inhibition alleviates the cellular senescence-associated ... - PNAS
Nov 2, 2015 · JAK1/2 inhibitors reduced inflammation and alleviated frailty in aged mice. One possible mechanism contributing to reduced frailty is SASP inhibition.
[46]
p53 and rapamycin are additive - Oncotarget
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Effect of rapamycin on aging and age-related diseases—past and ...
Oct 10, 2020 · ... cells. Two groups independently and simultaneously reported in 2015 that rapamycin reduced SASP produced by senescent human fibroblasts.<|control11|><|separator|>
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Metformin mitigates SASP secretion and LPS-triggered hyper ...
Apr 24, 2023 · Our study demonstrates that metformin mitigates DOX-induced endothelial senescence phenotype and ameliorates the hyper-inflammatory response to LPS.
[49]
Apigenin suppresses the senescence-associated secretory ... - NIH
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[50]
Natural Products Acting as Senolytics and Senomorphics Alleviate ...
Mitochondrial dysfunction and increased ROS levels are present in aging ... Anti-Inflammatory Effects of Resveratrol in Patients with Cardiovascular Disease: A ...
[51]
Prophylactic and long-lasting efficacy of senolytic CAR T cells ...
Jan 24, 2024 · Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving ...
[52]
Senolytic CAR T cells reverse senescence-associated pathologies
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Prophylactic and long-lasting efficacy of senolytic CAR T cells ...
We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR ...
[54]
therapeutic potential of uPAR-CAR T cells for senescence-related ...
Interestingly, uPAR-targeting senolytic CAR-T cells have been shown to effectively eliminate senescent cells and ameliorate senescence-associated liver diseases ...
[55]
Targeting senescent cells with NKG2D-CAR T cells - Nature
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Sphingomyelin nanosystems decorated with TSP-1 derived peptide ...
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[57]
[PDF] THESE DE DOCTORAT DE
Senescent cancer cells can escape and become more aggressive. Targeting these cells with senolytic/senostatic agents, like 4N1Ks peptide, can prevent relapse.
[58]
Regulation of senescence escape by TSP1 and CD47 ... - NIH
Feb 27, 2019 · In this study, we characterized this emergence and showed that senescent cells favor tumor growth and metastasis, in vitro and in vivo.Missing: senolytics mimetics 4N1K
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Nanovaccine loaded with seno-antigen target senescent cells to ...
We developed a novel nanovaccine (GK-NaV) loaded with seno-antigen that is self-assembled from the fusion of cationic protein (K36) and seno-antigen peptide ( ...
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uPAR-targeted senolytic delivery to enhance cancer therapy
This study aimed to develop a targeted nano-system for delivering the senolytic agent, dasatinib to target uPAR-overexpressing senescent cells induced by ...
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A Self-Assembling Senolytic Prodrug with Enhanced Bioavailability ...
Oct 1, 2025 · Senolytic therapy, which targets and selectively eliminates senescent cells, has emerged as a promising strategy for treating various ...Missing: hybrid | Show results with:hybrid
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Nano-encapsulated senolytic cocktail attenuates germ cell ...
Apr 18, 2025 · We report that a nano-encapsulated senolytic D + Q cocktail efficiently improves the quality of post-ovulatory aging oocyte in vitro and follicle quantity in ...Missing: hybrid vaccines<|separator|>
[63]
Targeted clearance of senescent cells using an antibody-drug ...
Oct 13, 2021 · ... selectively kill senescent cells with no toxicity to proliferating cells. This proves the feasibility of antibody-based targeted senolytics ...
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Targeting the senescent surfaceome through DPP4 antibody ...
A nanoparticle targeting DPP4 overexpression in the senescent surfaceome is designed, synthesized, and characterized to target senescent cancer cells.Missing: nanotherapies | Show results with:nanotherapies
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Targeting Senescence: A Review of Senolytics and Senomorphics ...
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Senolytics & Age-Related Diseases: A New Era in Drug Discovery
Jun 25, 2025 · In this article, we explore the growing potential of therapies that target cellular senescence, particularly senolytics, ...
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Targeting Aging Hallmarks with Monoclonal Antibodies: A New Era ...
mAbs and ADCs bind to specific surface markers, hence targeting senescent cells (depicted in green). The interaction of MAbs or ADCs initiates immune ...
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A second generation of senotherapies: the development of targeted ...
Jun 28, 2024 · The current senolytics and senomorphics are often repurposed drugs with several off-target effects that can induce toxicity. These drugs can ...Missing: fewer | Show results with:fewer
[69]
The Future of Aging Research - Cedars-Sinai
Apr 11, 2025 · Senolytics have shown promise in reducing senescent cell burden, improving symptoms, and stalling onset or progression of more than 70 age- ...
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Senolytics Improve Physical Function and Increase Lifespan in Old ...
Jan 9, 2019 · Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, ...
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Senescent cells as a target for anti-aging interventions
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Insights into targeting cellular senescence with senolytic therapy
Preclinical research has revealed that age-related diseases are caused by SnCs accumulation, and that pharmacologically eliminating SnCs can treat pathologies ...
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Using proteolysis-targeting chimera technology to reduce navitoclax ...
Apr 24, 2020 · We report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl ...
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Strategies to Reduce the On-Target Platelet Toxicity of Bcl-xL Inhibitors
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[75]
Senescence in Wound Repair: Emerging Strategies to Target ...
This review will explore emerging roles for cellular senescence in normal and pathological wound repair, highlighting areas of potential therapeutic ...
[76]
Does cellular senescence hold secrets for healthier aging?
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Cellular senescence in brain aging and neurodegeneration
Furthermore, human astrocytes respond to ionizing radiation by increasing p16Ink4a, p21CIP1/WAF1, SA-β-gal, and SASP levels. This insight clarifies the ...Review Article · 2. Accumulation Of Senescent... · 4. Accumulation And Function...
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Discovery, development, and future application of senolytics ...
Feb 29, 2020 · The discovery of senolytic drugs, agents that selectively eliminate senescent cells, created a new route for alleviating age-related dysfunction ...Missing: definition | Show results with:definition
[79]
NCT05758246 | Senolytics To slOw Progression of Sepsis (STOP ...
The long-term goal is to test the clinical efficacy of senolytic therapies to reduce progression to and severity of sepsis in older patients.
[80]
Evaluation of exploratory fluid biomarkers from a phase 1 senolytic ...
In brief summary, five individuals with early-stage AD were recruited to participate in an open-label trial which provided dasatinib (100 mg, Sprycel, Bristol ...
[81]
Killing wisely: precision senolytics in the age of frailty
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[82]
Age reprogramming: Innovations and ethical considerations for ...
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[83]
Development and Application of a Senolytic Predictor for Discovery ...
Jun 19, 2025 · First of all, this study successfully developed a machine learning-based senolytic predictor using comprehensive phenotype-based data.
[84]
Senescent cells as a target for anti-aging interventions:...
Mar 19, 2025 · This review gives an update of the current status in the discovery and development of senolytic therapies, and their translational progress from preclinical to ...
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Translating the Biology of Aging into New Therapeutics for ...
Using urokinase-type plasminogen activator receptor (uPAR) as antigen, it has recently been shown that CAR-T cells can actively remove senescent cells and ...
[86]
Targeting Cellular Senescence for Healthy Aging: Advances in ...
Sep 19, 2025 · When senescent cells exhibit mitochondrial dysfunction, it leads to an altered cellular redox state. This provides an opportunity for senolytic ...